title: Synthesis and SAR study of novel 3,3-diphenyl-1,3-dihydroindol-2-one derivatives as potent eIF2·GTP·Met-tRNAiMet ternary complex inhibitors.
abstract: The growing recognition of inhibition of translation initiation as a new and promising paradigm for mechanism-based anti-cancer therapeutics is driving the development of potent, specific, and druggable inhibitors. The 3,3-diaryloxindoles were recently reported as potential inhibitors of the eIF2·GTP·Met-tRNAi(Met) ternary complex assembly and 3-{5-tert-butyl-2-hydroxyphenyl}-3-phenyl-1,3-dihydro-2H-indol-2-one #1181 was identified as the prototypic agent of this chemotype. Herein, we report our continuous effort to further develop this chemotype by exploring the structural latitude toward different polar and hydrophobic substitutions. Many of the novel compounds are more potent than the parent compound in the dual luciferase ternary complex reporter assay, activate downstream effectors of reduced ternary complex abundance, and inhibit cancer cell proliferation in the low μM range. Moreover, some of these compounds are decorated with substituents that are known to endow favorable physicochemical properties and as such are good candidates for evaluation in animal models of human cancer.
authors.affiliation: Laboratory for Translational Research, Harvard Medical School, One Kendall Square, Building 600, 3rd Floor, Cambridge, MA 02139, USA.
authors.forename: Séverine
authors.initials: S
authors.lastname: Denoyelle
authors.forename: Ting
authors.initials: T
authors.lastname: Chen
authors.forename: Hongwei
authors.initials: H
authors.lastname: Yang
authors.forename: Limo
authors.initials: L
authors.lastname: Chen
authors.forename: Yingzhen
authors.initials: Y
authors.lastname: Zhang
authors.forename: José A
authors.initials: JA
authors.lastname: Halperin
authors.forename: Bertal H
authors.initials: BH
authors.lastname: Aktas
authors.forename: Michael
authors.initials: M
authors.lastname: Chorev
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D015852:Eukaryotic Initiation Factor-2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006160:Guanosine Triphosphate / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D015394:Molecular Structure; D012358:RNA, Transfer, Met / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D015852:Eukaryotic Initiation Factor-2; D007211:Indoles; D012358:RNA, Transfer, Met; D006160:Guanosine Triphosphate
keywords: 3,3-Diaryloxindole derivatives; ISTFANUWXAQLTD-UHFFFAOYSA-N; Inhibition of cancer cell proliferation; Mechanistic assays; Ternary complex TC; Translation initiation TI